Group V Phospholipase A(2) Mediates Endothelial Dysfunction and Acute Lung Injury Caused by Methicillin-Resistant Staphylococcus Aureus

Lung endothelial dysfunction is a key feature of acute lung injury (ALI) and clinical acute respiratory distress syndrome (ARDS). Previous studies have identified the lipid-generating enzyme, group V phospholipase A2 (gVPLA(2)), as a mediator of lung endothelial barrier disruption and inflammation. The current study aimed to determine the role of gVPLA(2) in mediating lung endothelial responses to methicillin-resistant Staphylococcus aureus (MRSA, USA300 strain), a major cause of ALI/ARDS. In vitro studies assessed the effects of gVPLA(2) inhibition on lung endothelial cell (EC) permeability after exposure to heat-killed (HK) MRSA. In vivo studies assessed the effects of intratracheal live or HK-MRSA on multiple indices of ALI in wild-type (WT) and gVPLA(2)-deficient (KO) mice. In vitro, HK-MRSA increased gVPLA(2) expression and permeability in human lung EC. Inhibition of gVPLA(2) with either the PLA2 inhibitor, LY311727, or with a specific monoclonal antibody, attenuated the barrier disruption caused by HK-MRSA. LY311727 also reduced HK-MRSA-induced permeability in mouse lung EC isolated from WT but not gVPLA(2)-KO mice. In vivo, live MRSA caused significantly less ALI in gVPLA(2) KO mice compared to WT, findings confirmed by intravital microscopy assessment in HK-MRSA-treated mice. After targeted delivery of gVPLA(2) plasmid to lung endothelium using ACE antibody-conjugated liposomes, MRSA-induced ALI was significantly increased in gVPLA(2)-KO mice, indicating that lung endothelial expression of gVPLA(2) is critical in vivo. In summary, these results demonstrate an important role for gVPLA(2) in mediating MRSA-induced lung EC permeability and ALI. Thus, gVPLA(2) may represent a novel therapeutic target in ALI/ARDS caused by bacterial infection.